Obesity inhibits hypothalamic activation and luteinizing hormone dynamics through Sox-2-dependent demyelination

Obesity is a well – recognized cause of hypothalamic - pituitary hypogonadism. However, the activation patterns of whole hypothalamic neurons, the dynamic secretion of luteinizing hormone (LH) pulses and surges, and the underlying mechanisms remain unclear. We combined c-fos-based TetTag labeling, tissue clearing, and 3D imaging to map global hypothalamic neuronal activation in diet-induced obese mice. Serial blood sampling revealed how metabolic stress disrupts LH secretion dynamics—specifically its pulsatility across the estrous cycle and preovulatory surge. We further profiled transcriptional changes in activated neurons using fluorescence-activated cell sorting, Smart-seq2 sequencing, and Ingenuity Pathway Analysis. 3D imaging provides the first direct evidence that obesity globally suppresses neuronal activation in key reproductive nuclei: GFP + neuron counts drop significantly in the anteroventral periventricular nucleus (525 vs. 1994), preoptic area (1821 vs. 2542), and arcuate nucleus (447 vs. 1144) versus controls. Obesity also disrupts the temporal organization of LH hormone secretion—reducing pulse frequency (4.75 ± 1.09 vs. 6.2 ± 1.4), mean and basal LH during proestrus, and abolishing the LH surge (25.0% vs. 66.7%; peak LH ~3.0 vs. ~7.0 ng/ml). Transcriptomic analysis identifies Sox2-mediated demyelination as the top systems-level change, evidenced by downregulation of myelin genes (e.g., Plp1, Mag) and histological confirmation of axonal loss and demyelination in these nuclei. In conclusion, these findings might uncover a previously unknown structural cause of obesity-related infertility: Sox2-mediated hypothalamic demyelination—shifting focus from functional neuroendocrine suppression to structural damage and highlighting myelin repair as a promising therapeutic strategy for restoring fertility in metabolic disorders. Schematic illustration of obesity-induced hypothalamic-pituitary hypogonadism via Sox2-mediated demyelination. HFD-induced obesity might cause Sox2-mediated demyelination in activated hypothalamic neurons—especially in the AVPV and POA—impairing hypothalamic activation. This might disrupt dynamic LH release across the estrous cycle: LH pulses decline during proestrus, and the preovulatory LH surge occurs less frequently. As a result, ovarian dysfunction arises, featuring polycystic ovaries with multiple small antral follicles and irregular cycles dominated by prolonged diestrus. • 3D TetTag imaging reveals global hypothalamic suppression in obese mice. • Obesity disrupts proestrus LH pulsatility and blunts the preovulatory surge. • Unbiased transcriptomics identifies Sox2-mediated hypothalamic demyelination.